Streptococcus pneumoniae causes more fatal infections world-wide than almost any other pathogen (refs. 1, 2,--a list of the references appears at the end of the disclosure; and each reference is hereby incorporated herein by reference). In the U.S.A., deaths caused by S. pneumoniae rival in numbers those caused by AIDS (ref. 1). In the U.S.A., most fatal pneumococcal infections occur in individuals over 65 years of age, in whom S. pneumoniae is the most common cause of community-acquired pneumonia. In the developed world, most pneumococcal deaths occur in the elderly, or in immunodeficient patents including those with sickle cell disease. In the less-developed areas of the world, pneumococcal infection is one of the largest causes of death among children less than 5 of age (refs. 3, 4, 5, 6). The increase in the frequency of multiple antibiotic resistance among pneumococci and the prohibitive cost of drug treatment in poor countries make the present prospects for control of pneumococcal disease problematical (refs. 7, 8, 9).
The reservoir of pneumococci that infect man is maintained primarily via nasopharyngeal human carriage. Humans acquire pneumococci through aerosols or by direct contact. Pneumococci first colonize the upper airways and can remain in nasal mucosa for weeks or months. As many as 50% or more of young children and the elderly are colonized. In most cases, this colonization results in no apparent infection (refs. 10, 11, 12). Studies of outbreak strains have suggested that even highly virulent strains can colonize without causing disease (refs. 13, 14, 15, 16). These expectations have been recently confirmed using molecular probes to fingerprint individual clones (M. J. Crain, personal communication to one of the inventors). In some individuals, however, the organism carried in the nasopharynx can give rise to symptomatic sinusitis or middle ear infections. If pneumococci are aspirated into the lung, especially with food particles or mucus, they can cause pneumonia. Infections at these sites generally shed some pneumococci into the blood where they can lead to sepsis, especially if they continue to be shed in large numbers from the original focus of infection. Pneumococci in the blood can reach the brain where they can cause meningitis. Although pneumococcal meningitis is less common than other infections caused by these bacteria, it is particularly devastating; some 10% of patients die and greater than 50% of the remainder have life-long neurological sequelae (refs. 17, 18).
In elderly adults, the present 23-valent capsular polysaccharide vaccine is about 60% effective against invasive pneumococcal disease with strains of the capsular types included in the vaccine (refs. 19, 20). The 23-valent vaccine is not effective in children less than 2 years of age because of their inability to make adequate responses to most polysaccharides (refs. 21, 22). Improved vaccines that can protect children and adults against invasive infections with pneumococci would help reduce some of the most deleterious aspects of this disease. A vaccine that protected against disease but did not reduce pneumococcal carriage rates would not, however, be expected to control the disease in immuno-compromised (ref. 20) and in unimmunized individuals. Such a vaccine would also not be expected to affect the rates of infection in immunized children prior to the development of an adequate anti-vaccine response.
A strategy that could control infections in all of these individuals would be any form of immunization that prevented or greatly reduced carriage, and hence transmission of pneumococci. In the case of immunization of young children with Haemophilus influenzae group b polysaccharide-protein conjugates, it has been observed that carriage is reduced from about 4% to less than 1%, (ref. 23), a possible explanation of concomitant herd immunity (ref. 24). If a vaccine could prevent colonization by pneumococci, such vaccine would be expected to prevent virtually all pneumococcal infections in the immunized patients. Since even unimmunized patients must acquire pneumococci from others, a vaccine that reduced carriage should reduce infections in immuno-compromised as well as unimmunized patients. In fact, an aggressive immunization program, coupled with antibiotic treatment of demonstrated carriers, might be able to largely eliminate the human reservoir of this organism. It may not be possible, however, to totally eliminate pneumococci since there are a number of reports that they have been found in laboratory rodents (ref. 25). Whether these pneumococci are infectious for man, easily transmittable to man, or even pathogens in wild rodents is not known. S. pneumoniae does not live free in the environment.
Although intramuscular immunization with capsular polysaccharide vaccines has been effective at reducing the incidence of pneumococcal sepsis in the elderly (ref. 20), it has not been reported to affect pneumococcal carriage rates in children up to 54 months of age (refs 26, 27). Whether the conjugate vaccine will reduce carriage in children is not known. Thus, the search for a vaccine which can reduce rates of nasopharyngeal carriage must include an examination of non-capsular antigens. Since immunity to carriage would be expected to operate at the mucosal surface, any attempt to identify antigens for vaccines against carriage should include immunizations designed to elicit mucosal immune responses. Accordingly, the intranasal immunization or administration with pneumococcal proteins, as in the present invention has not, it is believed been heretofore disclosed or suggested or, in addition, the evaluation of polysaccharide-protein conjugates, as in the present disclosure, has not it is believed been heretofore taught or suggested.